The present invention relates to cycloalkyl substituted ketoamide derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such ketoamide derivatives are inhibitors of serine and cysteine proteases. Particularly, such ketoamide derivatives are inhibitors of cysteine proteases of the papain superfamily. More particularly, the ketoamides of the present invention are inhibitors of cathepsin family cysteine proteases such as cathepsin K. Such ketoamide derivatives are useful in the treatment of diseases associated with serine and cysteine protease activity, more particularly, in the treatment of diseases associated with cathepsin family cysteine proteases, for instance in the treatment of diseases associated with cathepsin K activity.
Osteoclasts are multinuclear cells of hematopoietic lineage, which function in the process of bone resorption. Typically, bone resorption proceeds as follows: The osteoclasts adhere to a bone surface and form a tight sealing zone. This activity is followed by extensive membrane ruffling on the surface of the osteoclasts. Such action creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way a resorption pit is formed. At the completion of this cycle osteoblasts remodel the bone; that is, deposit a new protein matrix, which is subsequently mineralized at this zone.
Normally, a balance exists between the processes of bone resorption and new bone formation during remodeling. This normal balance of bone resorption and bone formation may be disrupted resulting in a net loss of bone in each cycle of remodeling. Such net bone loss may lead to osteoporosis. Osteoporosis is characterized by reduced bone mass and disruptions in the microarchitecture of the bone. These characteristics may lead to fractures, which can result from a minimal amount of trauma. Typical sites of fractures include vertebral bodies, distal radius, and the proximal femur. However, because those suffering from osteoporosis have general skeletal weakness, fractures may occur at other sites.
Since osteoporosis is characterized by an increase in bone resorption with respect to bone remodeling, therapeutic agents that suppress bone resorption would be expected to provide a suitable treatment for osteoporosis. Administration of estrogens or calcitonin has been the bone resorption suppression treatment typically employed. However, these treatments do not always achieve the desired effect Consequently, there is a continuing need for therapeutic agents which can attentuate bone resorption in a subject in need of such attenuation.
Cathepsin K, which has also been called cathepsin O, cathepsin O2, and cathepsin X, is a member of the cysteine cathepsin family of enzymes, which are part of the papain superfamily of cysteine proteases. Other distinct cysteine protease cathepsins, designated cathepsin B, cathepsin C, cathepsin F, cathepsin H, cathepsin L, cathepsin O, cathepsin S, cathepsin V (also called L2), cathepsin W, & cathepsin Z (also called cathepsin X), have also been described in the literature. Cathepsin K polypeptide and the cDNA encoding such polypeptide have been disclosed in U.S. Pat. No. 5,501,969. A crystal structure for cathepsin K has also been disclosed in PCT Patent Application WO 97/16177, published May 9, 1997. It has been reported that cathepsin K is abundantly expressed in osteoclasts under normal conditions and may be the major cysteine protease present in these cells. (See Tezuka, et al., J. Biol. Chem., 1994, 269, 1106; Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi, et al., FEBS Lett., 1995, 357,129.) This abundant selective expression of cathepsin K in osteoclasts suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, such as osteoporosis.
The selective inhibition of cathepsin K may also be useful in treating other diseases. Such disorders include autoimmune diseases such as rheumatoid arthritis, osteoarthritis, neoplastic diseases, parasitic diseases, and atherosclerosis. For instance, cathepsin K is expressed in the synovium and synovial bone destruction sites of patients with rheumatoid arthritis (see Votta, B. J. et al.; J. Bone Miner. Res. 1997, 12, 1396; Hummel, K. M. et al., J. Rheumatol. 1998, 25, 1887; Nakagawa, T. Y. et al., Immunity 1999, 10, 207; Otsuka, T. et al., S. J. Antibiot 1999, 52, 542; Li, Z. et al, Biochemistry 2000, 39, 529; Diaz, A. et al, Mol. Med. 2000, 6, 648; Moran, M. T. et al., Blood 2000, 96, 1969). Cathepsin K levels are elevated in chondroclasts of osteoarthritic synovium (See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588; Lang, A. et al., J. Rheumatol. 2000, 27, 1970). Neoplastic cells also have been shown to express cathepsin K (see Littlewood-Evans, A. J. et al, J. A. Cancer Res. 1997, 57, 5386; Komarova, E. A., et al., Oncogene 1998, 17, 1089; Santamaria, I., et al., Cancer Res. 1998, 58, 1624; Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460; Kirschke, H. et al., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M. et al., Clin. Cancer Res. 2000, 6, 2064). Cysteine protease inhibitors have been suggested as chemotherapy for parasitic diseases (see McKerrow, J. H. Int. J. Parasitol. 1999, 29, 833; Selzer, P. M. et al., Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11015; Caffrey, C. R. et al, Curr. Drug Targets 2000, 1, 155; Du, X. et al., Chem. Biol. 2000, 7, 733; Hanspal, M. Biochim. Biophys. Acta 2000, 1493, 242; Werbovetz, K. A. Curr. Med. Chem. 2000, 7, 835). Elastolytic cathepsins S and K are shown to be expressed in human atheroma (see Sukhova, G. K. et al., J. Clin. Invest. 1998, 102, 576-583; Parks, W. C. J. Clin. Invest. 1999, 104, 1167; Shi, G.-P. et al., J. Clin. Invest 1999, 104, 1191; Cao, H. et al., J. Hum. Genet. 2000, 45, 94).
The present inventors have now discovered novel cycloalkyl substituted ketoamide derivative compounds, which are inhibitors of serine and cysteine protease activities, more particularly, cathepsin family cysteine protease activities, and most particularly, cathepsin K activity. Such ketoamide derivatives are useful in the treatment of disorders associated with serine and cysteine protease activity, including osteoporosis, Paget's disease, hypercalcemia of malignancy, metabolic bone disease, osteoarthritis, rheumatoid arthritis, periodontitis, gingivitis, atherosclerosis, and neoplastic diseases associated with cathepsin K activity.